Eosinophilic gastrointestinal diseases (EGIDs) are a spectrum of diseases characterized by eosinophilic inflammation of the gastrointestinal tract. In the past decade, there has been a dramatic increase in the incidence of EGIDs, particularly eosinophilic esophagitis (EE). EGIDs, including eosinophilic gastroenteritis (EG) and EE, are commonly associated with food and aeroallergen hypersensitivity. Most EGID patients have numerous food allergies, and in many patients an amino acid based elemental diet is an effective treatment. This suggests that EGID pathogenesis is due to food allergen driven eosinophilic inflammation. [unreadable] [unreadable] At present, there are major gaps in our understanding of, and ability to effectively treat EGIDs. To address both treatment and pathogenesis questions, we have recently completed a clinical trial of omalizumab (therapeutic monoclonal anti-IgE) for eosinophilic gastroenteritis. This study asks two major questions: [unreadable] 1. Are anti-IgE therapeutics of clinical utility in eosinophilic gastrointestinal diseases?[unreadable] 2. Is the eosinophilic inflammation characteristic of EGIDs an IgE dependent process?[unreadable] [unreadable] A clinical trial of omalizumab was performed in which 9 subjects with EGIDs received omalizumab every 2 weeks for 16 weeks while other therapy was held constant. Blood absolute eosinophil counts, tissue eosinophil counts, symptom scores, and free IgE were serially measured. Allergen skin testing, and flow cytometry for basophil activation and Fc&#949;RI were determined at baseline and at week 16. Omalizumab was associated with a decrease in absolute eosinophil counts at both the 16 week (34%, p=0.004) and combined weeks 12-16 (42%, p=0.012) time points. Tissue eosinophils decreased in the duodenum (59%) and gastric antrum (69%), but did not reach statistical significance (p=0.074 and 0.098, respectively). Esophageal eosinophil counts remained unchanged. Basophil and dendritic cell Fc&#949;RI expression, and free IgE were all significantly decreased (p<0.005). Omalizumab increased the concentration of allergen required to trigger half-maximal basophil activation by 170-fold. Allergen skin test wheal and erythema responses decreased by 78% and 82%, respectively. Symptom scores were decreased at both the midstudy (63%) and end of study (70%) time points (p<0.005 for both). These results demonstrate that IgE-mediated processes contribute to the generation of eosinophilic inflammation in EGIDs, and suggest that anti-IgE therapy may be effective in these disorders.[unreadable] [unreadable] Omalizumab is a humanized anti-IgE monoclonal antibody approved for use in allergic asthma. Anti-IgE therapy reduces the concentration of circulating free IgE, blocks IgE binding to both Fc&#949;RI and CD23, and down regulates surface Fc&#949;RI on mast cells, basophils and dendritic cells. Because of the multiple actions of anti-IgE therapy that affect antigen presenting cells (APCs), it has been postulated that anti-IgE therapy may have immunomodulatory activity on T cells. We hypothesized two distinct mechanisms whereby anti-IgE therapy could inhibit allergen specific Th2 responses. First, anti-IgE down regulates Fc&#949;RI on dendritic cells and blocks CD23 mediated allergen binding to APCs, thereby inhibiting IgE facilitated Ag capture by APCs, which in turn could result in decreased allergen specific T cell activation. Second, IgE signaling of anti-IgE inhibits mast cell and basophil activation in vivo, which may decrease IL-4 expression, the lack of which could inhibit nave T cell differentiation into Th2 cells. To test this hypothesis, we assessed anti-IgE immunomodulation of allergen specific T cell responses during the above clinical trial of omalizumab in subjects with eosinophilic gastroenteritis and food allergy. Four allergen specific T cell responses (proliferation, dose response, precursor frequency, and cytokine expression) were measured using flow cytometry. In contradistinction to the hypothesis, we found that 16 weeks of anti-IgE therapy had no effect on allergen specific proliferation, precursor frequencies, or cytokine production, and yielded a small augmentation (not reduction) of the allergen dose response. In sum, we found no evidence to support the concept that anti-IgE therapy has an immunomodulatory or inhibitory effect on allergen specific T cells. As such, these data do not support a major role for IgE mediated Ag focusing in augmenting allergen specific T cell responses in vivo.